Project Summary/Abstract The objective of this proposal is to investigate the functional roles of Suv420h1 histone methyltransferase and the associated H4K20me3 modification in the regulation of tumorigenesis and therapeutic response. Among the multitude of epigenetic changes, the loss of H4K20me3 is a hallmark of cancer. Reduced levels of H4K20me3 correlate with cancer progression and poor therapeutic response in many human cancers. Although abundant literature suggests that H4K20me3 is associated with tumorigenesis, it remains unknown whether changes in Suv420h1 expression and H4K20me3 modification play a causal role in tumorigenesis and therapeutic response. Recently, I have discovered that MYC actively suppresses Suv420h1 expression to prevent the formation of H4K20me3 and block the induction of senescence. Senescence is known to be is a critical barrier to tumorigenesis as well as a key determinant of therapeutic response. Thus, I hypothesize that Suv420h1 is a critical tumor suppressor in MYC-driven tumorigenesis by modulating gene expression and chromatin accessibility, and driving senescence induction. Consequently, suppression of Suv420h1 and downregulation of H4K20me3 accelerate tumorigenesis and also contribute to therapeutic resistance. In order to causally and mechanistically test this hypothesis, I will integrate multiple genomics technologies to interrogate how Suv420h1 regulates chromatin accessibility and gene expression and further test in vivo using the well-established MYC-driven lymphoma models. I will test three specific aims. AIM 1) Investigate how modulation of Suv420h1 activity influences the gene expression and chromatin accessibility of E-myc lymphoma; AIM 2) Examine in vivo whether modulation of Suv420h1 expression influences tumor initiation in E-myc lymphoma; and AIM 3) Determine whether modulation of Suv420h1 influences therapeutic sensitivity in MYC-driven lymphoma. With the successful implementation of this proposal, I will reveal the critical role of Suv420h1/H4K20me3 in tumorigenesis and therapeutic response. To ensure the success of the proposed studies and my career development, I have assembled an impressive team of advisors and collaborators with expertise in cancer biology, epigenomics, and molecular imaging. The training and the guidance will contribute substantially to my transition to be an independent investigator.